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Published in: neurogenetics 2/2005

01-05-2005 | Original Article

A genome-wide scan provides evidence for loci influencing a severe heritable form of common migraine

Authors: R. A. Lea, D. R. Nyholt, R. P. Curtain, M. Ovcaric, R. Sciascia, C. Bellis, J. MacMillan, S. Quinlan, R. A. Gibson, L. C. McCarthy, J. H. Riley, Y. J. Smithies, S. Kinrade, L. R. Griffiths

Published in: Neurogenetics | Issue 2/2005

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Abstract

Migraine is a prevalent neurovascular disease with a significant genetic component. Linkage studies have so far identified migraine susceptibility loci on chromosomes 1, 4, 6, 11, 14, 19 and X. We performed a genome-wide scan of 92 Australian pedigrees phenotyped for migraine with and without aura and for a more heritable form of “severe” migraine. Multipoint non-parametric linkage analysis revealed suggestive linkage on chromosome 18p11 for the severe migraine phenotype (LOD*=2.32, P=0.0006) and chromosome 3q (LOD*=2.28, P=0.0006). Excess allele sharing was also observed at multiple different chromosomal regions, some of which overlap with, or are directly adjacent to, previously implicated migraine susceptibility regions. We have provided evidence for two loci involved in severe migraine susceptibility and conclude that dissection of the “migraine” phenotype may be helpful for identifying susceptibility genes that influence the more heritable clinical (symptom) profiles in affected pedigrees. Also, we concluded that the genetic aetiology of the common (International Headache Society) forms of the disease is probably comprised of a number of low to moderate effect susceptibility genes, perhaps acting synergistically, and this effect is not easily detected by traditional single-locus linkage analyses of large samples of affected pedigrees.
Literature
1.
go back to reference Headache Classification Committee of the International Headache Society (1988) Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 8(Suppl 7):19–28 Headache Classification Committee of the International Headache Society (1988) Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 8(Suppl 7):19–28
2.
go back to reference Russell MB, Iselius L, Olesen J (1996) Migraine without aura and migraine with aura are inherited disorders. Cephalalgia 16(5):305–309 Russell MB, Iselius L, Olesen J (1996) Migraine without aura and migraine with aura are inherited disorders. Cephalalgia 16(5):305–309
3.
go back to reference Honkasalo ML, Kaprio J, Winter T, Heikkila K, Sillanpaa M, Koskenvuo M (1995) Migraine and concomitant symptoms among 8167 adult twin pairs. Headache 35:70–78 Honkasalo ML, Kaprio J, Winter T, Heikkila K, Sillanpaa M, Koskenvuo M (1995) Migraine and concomitant symptoms among 8167 adult twin pairs. Headache 35:70–78
4.
go back to reference Larsson B, Bille B, Pedersen NL (1995) Genetic influence in headaches: a Swedish twin study. Headache 35(9):513–519 Larsson B, Bille B, Pedersen NL (1995) Genetic influence in headaches: a Swedish twin study. Headache 35(9):513–519
5.
go back to reference Nyholt DR, Gillespie NA, Heath AC, Merikangas KR, Duffy DL, Martin NG (2004) Latent class analysis does not support migraine with aura and migraine without aura as separate entities. Genet Epidemiol 26:231–244CrossRef Nyholt DR, Gillespie NA, Heath AC, Merikangas KR, Duffy DL, Martin NG (2004) Latent class analysis does not support migraine with aura and migraine without aura as separate entities. Genet Epidemiol 26:231–244CrossRef
6.
go back to reference Kalfakis N, Panas M, Vassilopoulos D, Malliara-Loulakaki S (1996) Migraine with aura: segregation analysis and heritability estimation. Headache 36(5):320–322 Kalfakis N, Panas M, Vassilopoulos D, Malliara-Loulakaki S (1996) Migraine with aura: segregation analysis and heritability estimation. Headache 36(5):320–322
7.
go back to reference Wessman M, Kallela M, Kaunisto MA, Marttila P, Sobel E, Hartiala J, Oswell G, Leal SM, Papp JC, Hamalainen E, Broas P, Joslyn G, Hovatta I, Hiekkalinna T, Kaprio J, Ott J, Cantor RM, Zwart JA, Ilmavirta M, Havanka H, Farkkila M, Peltonen L, Palotie A (2002) A susceptibility locus for migraine with aura, on chromosome 4q24. Am J Hum Genet 70(3):652–662 Wessman M, Kallela M, Kaunisto MA, Marttila P, Sobel E, Hartiala J, Oswell G, Leal SM, Papp JC, Hamalainen E, Broas P, Joslyn G, Hovatta I, Hiekkalinna T, Kaprio J, Ott J, Cantor RM, Zwart JA, Ilmavirta M, Havanka H, Farkkila M, Peltonen L, Palotie A (2002) A susceptibility locus for migraine with aura, on chromosome 4q24. Am J Hum Genet 70(3):652–662
8.
go back to reference Lea RA, Shepherd AG, Curtain RP, Nyholt DR, Quinlan S, Brimage PJ, Griffiths LR (2002) A typical migraine susceptibility region localizes to chromosome 1q31. Neurogenetics 4(1):17–22CrossRefPubMed Lea RA, Shepherd AG, Curtain RP, Nyholt DR, Quinlan S, Brimage PJ, Griffiths LR (2002) A typical migraine susceptibility region localizes to chromosome 1q31. Neurogenetics 4(1):17–22CrossRefPubMed
9.
go back to reference Bjornsson A, Gudmundsson G, Gudfinnsson E, Hrafnsdottir M, Benedikz J, Skuladottir S, Kristjansson K, Frigge ML, Kong A, Stefansson K, Gulcher JR (2003) Localization of a gene for migraine without aura to chromosome 4q21. Am J Hum Genet. Sep 25 (epublication) Bjornsson A, Gudmundsson G, Gudfinnsson E, Hrafnsdottir M, Benedikz J, Skuladottir S, Kristjansson K, Frigge ML, Kong A, Stefansson K, Gulcher JR (2003) Localization of a gene for migraine without aura to chromosome 4q21. Am J Hum Genet. Sep 25 (epublication)
10.
go back to reference Carlsson A, Forsgren L, Nylander PO, Hellman U, Forsman-Semb K, Holmgren G, Holmberg D, Holmberg M (2002) Identification of a susceptibility locus for migraine with and without aura on 6p12.2–p21.1. Neurology 59(11):1804–1807 Carlsson A, Forsgren L, Nylander PO, Hellman U, Forsman-Semb K, Holmgren G, Holmberg D, Holmberg M (2002) Identification of a susceptibility locus for migraine with and without aura on 6p12.2–p21.1. Neurology 59(11):1804–1807
11.
go back to reference Cader ZM, Noble-Topham S, Dyment DA, Cherny SS, Brown JD, Rice GP, Ebers GC (2003) Significant linkage to migraine with aura on chromosome 11q24. Hum Mol Genet 12(19):2511–2517 Cader ZM, Noble-Topham S, Dyment DA, Cherny SS, Brown JD, Rice GP, Ebers GC (2003) Significant linkage to migraine with aura on chromosome 11q24. Hum Mol Genet 12(19):2511–2517
12.
go back to reference Soragna D, Vettori A, Carraro G, Marchioni E, Vazza G, Bellini S, Tupler R, Savoldi F, Mostacciuolo ML (2003) A locus for migraine without aura maps on chromosome 14q21.2–q22.3. Am J Hum Genet 72(1):161–167 Soragna D, Vettori A, Carraro G, Marchioni E, Vazza G, Bellini S, Tupler R, Savoldi F, Mostacciuolo ML (2003) A locus for migraine without aura maps on chromosome 14q21.2–q22.3. Am J Hum Genet 72(1):161–167
13.
go back to reference Nyholt DR, Lea RA, Goadsby PJ, Brimage PJ, Griffiths LR (1998) Familial typical migraine-linkage to chromosome 19p13 and evidence for genetic heterogeneity. Neurology 50:1428–1432 Nyholt DR, Lea RA, Goadsby PJ, Brimage PJ, Griffiths LR (1998) Familial typical migraine-linkage to chromosome 19p13 and evidence for genetic heterogeneity. Neurology 50:1428–1432
14.
go back to reference Jones KW, Ehm MG, Pericak-Vance MA, Haines JL, Boyd PR, Peroutka SJ (2001) Migraine with aura susceptibility locus on chromosome 19p13 is distinct from the familial hemiplegic migraine locus. Genomics 78(3):150–154 Jones KW, Ehm MG, Pericak-Vance MA, Haines JL, Boyd PR, Peroutka SJ (2001) Migraine with aura susceptibility locus on chromosome 19p13 is distinct from the familial hemiplegic migraine locus. Genomics 78(3):150–154
15.
go back to reference Nyholt DR, Curtain RP, Griffiths LR (2000) Familial typical migraine: significant linkage and localization of a gene to Xq24–28. Hum Genet 107(1):18–23 Nyholt DR, Curtain RP, Griffiths LR (2000) Familial typical migraine: significant linkage and localization of a gene to Xq24–28. Hum Genet 107(1):18–23
16.
go back to reference McCarthy LC, Hosford DA, Riley JH, Bird M, White NJ, Hewett DR, Peroutka SJ et al (2001) Single nucleotide polymorphism (SNP) alleles in the insulin receptor (INSR) gene are associated with migraine. Genomics 78(3):135–149 McCarthy LC, Hosford DA, Riley JH, Bird M, White NJ, Hewett DR, Peroutka SJ et al (2001) Single nucleotide polymorphism (SNP) alleles in the insulin receptor (INSR) gene are associated with migraine. Genomics 78(3):135–149
17.
go back to reference Peroutka SJ, Wilhoit T, Jones K (1997) Clinical susceptibility to migraine with aura is modified by dopamine D2 receptor (DRD2) NcoI alleles. Neurology 49:201–206 Peroutka SJ, Wilhoit T, Jones K (1997) Clinical susceptibility to migraine with aura is modified by dopamine D2 receptor (DRD2) NcoI alleles. Neurology 49:201–206
18.
go back to reference Lea R, Dohy A, Jordan K et al (2000) Evidence for allelic association of the dopamine beta-hydroxylase gene (DBH) with susceptibility to typical migraine. Neurogenetics 3(1):35–40 Lea R, Dohy A, Jordan K et al (2000) Evidence for allelic association of the dopamine beta-hydroxylase gene (DBH) with susceptibility to typical migraine. Neurogenetics 3(1):35–40
19.
go back to reference Lea RA, Ovcaric M, Sundholm J, Solyom L, Griffiths LR (2004) The methylenetetrahydrofolate reductase gene variant C677T influences susceptibility to migraine with aura. BMC Med 2:3 Lea RA, Ovcaric M, Sundholm J, Solyom L, Griffiths LR (2004) The methylenetetrahydrofolate reductase gene variant C677T influences susceptibility to migraine with aura. BMC Med 2:3
20.
go back to reference Miller SA, Dykes DD, Plensky HF (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16(3):1215PubMed Miller SA, Dykes DD, Plensky HF (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16(3):1215PubMed
21.
go back to reference Abecasis GR, Cherny SS, Cookson WO, Cardon LR (2002) Merlin-rapid analysis of dense genetic maps using sparse gene flow trees. Nat Genet 30(1):97–101CrossRefPubMed Abecasis GR, Cherny SS, Cookson WO, Cardon LR (2002) Merlin-rapid analysis of dense genetic maps using sparse gene flow trees. Nat Genet 30(1):97–101CrossRefPubMed
22.
go back to reference Kong A, Cox NJ (1997) Allele-sharing models: LOD scores and accurate linkage tests. Am J Hum Genet 61:1179–1188 Kong A, Cox NJ (1997) Allele-sharing models: LOD scores and accurate linkage tests. Am J Hum Genet 61:1179–1188
23.
go back to reference Nyholt DR (2000) All LODs are not created equal. Am J Hum Genet 67(2):282–288 Nyholt DR (2000) All LODs are not created equal. Am J Hum Genet 67(2):282–288
24.
go back to reference Ophoff RA, Terwindt GM, Vergouwe MN, Van Eijk R, Oefner PJ, Hoffman SM et al (1996) Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4. Cell 87:543–552CrossRefPubMed Ophoff RA, Terwindt GM, Vergouwe MN, Van Eijk R, Oefner PJ, Hoffman SM et al (1996) Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4. Cell 87:543–552CrossRefPubMed
25.
go back to reference De Fusco M, Marconi R, Silvestri L, Atorino L, Rampoldi L, Morgante L, Ballabio A, Aridon P, Casari G (2003) Haploinsufficiency of ATP1A2 encoding the Na+/K+ pump alpha2 subunit associated with familial hemiplegic migraine type 2. Nat Genet 33(2):192–196CrossRefPubMed De Fusco M, Marconi R, Silvestri L, Atorino L, Rampoldi L, Morgante L, Ballabio A, Aridon P, Casari G (2003) Haploinsufficiency of ATP1A2 encoding the Na+/K+ pump alpha2 subunit associated with familial hemiplegic migraine type 2. Nat Genet 33(2):192–196CrossRefPubMed
Metadata
Title
A genome-wide scan provides evidence for loci influencing a severe heritable form of common migraine
Authors
R. A. Lea
D. R. Nyholt
R. P. Curtain
M. Ovcaric
R. Sciascia
C. Bellis
J. MacMillan
S. Quinlan
R. A. Gibson
L. C. McCarthy
J. H. Riley
Y. J. Smithies
S. Kinrade
L. R. Griffiths
Publication date
01-05-2005
Publisher
Springer-Verlag
Published in
Neurogenetics / Issue 2/2005
Print ISSN: 1364-6745
Electronic ISSN: 1364-6753
DOI
https://doi.org/10.1007/s10048-005-0215-6

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